Effect of photobiomodulation on mitochondrial dynamics in peripheral nervous system in streptozotocin-induced type 1 diabetes in rats.

There is no effective treatment to halt peripheral nervous system damage in diabetic peripheral neuropathy. Mitochondria have been at the center of discussions as important factors in the development of neuropathy in diabetes. Photobiomodulation has been gaining clinical acceptance as it shows beneficial effects on a variety of nervous system disorders. In this study, the effects of photobiomodulation (904 nm, 45 mW, 6.23 J/cm2, 0.13 cm2, 60 ns pulsed time) on mitochondrial dynamics were evaluated in an adult male rat experimental model of streptozotocin-induced type 1 diabetes. Results presented here indicate that photobiomodulation could have an important role in preventing or reversing mitochondrial dynamics dysfunction in the course of peripheral nervous system damage in diabetic peripheral neuropathy. Photobiomodulation showed its effects on modulating the protein expression of mitofusin 2 and dynamin-related protein 1 in the sciatic nerve and in the dorsal root ganglia neurons of streptozotocin-induced type 1 diabetes in rats.

Pulsed Electromagnetic Fields Accelerate Sensorimotor Recovery Following Experimental Disc Herniation.

STUDY DESIGN: An experimental animal study. OBJECTIVE: The aim of this study was to investigate the effect of pulsed electromagnetic fields (PEMF) on recovery of sensorimotor function in a rodent model of disc herniation (DH). SUMMARY OF BACKGROUND DATA: Radiculopathy associated with DH is mediated by proinflammatory cytokines. Although we have demonstrated the anti-inflammatory effects of PEMF on various tissues, we have not investigated the potential therapeutic effect of PEMF on radiculopathy resulting from DH. METHODS: Nineteen rats were divided into three groups: positive control (PC; left L4 nerve ligation) (n = 6), DH alone (DH; exposure of left L4 dorsal root ganglion [DRG] to harvested nucleus pulposus and DRG displacement) (n = 6), and DH + PEMF (n = 7). Rodents from the DH + PEMF group were exposed to PEMF immediately postoperatively and for 3 hours/day until the end of the study. Sensory function was assessed via paw withdrawal thresholds to non-noxious stimuli preoperatively and 1 and 3 days postoperatively, and every 7 days thereafter until 7 weeks after surgery. Motor function was assessed via DigiGait treadmill analysis preoperatively and weekly starting 7 days following surgery until 7 weeks following surgery. RESULTS: All groups demonstrated marked increases in the left hindlimb response threshold postoperatively. However, 1 week following surgery, there was a significant effect of condition on left hindlimb withdrawal thresholds (one-way analysis of variance: F = 3.82, df = 2, P = 0.044) where a more rapid recovery to baseline threshold was evident for DH + PEMF compared to PC and DH alone. All groups demonstrated gait disturbance postoperatively. However, DH + PEMF rodents were able to regain baseline gait speeds before DH and PC rodents. When comparing gait parameters, DH + PEMF showed consistently less impairment postoperatively suggesting that PEMF treatment was associated with less severe gait disturbance. CONCLUSION: These data demonstrate that PEMF accelerates sensorimotor recovery in a rodent model of DH, suggesting that PEMF may be reasonable to evaluate for the clinical management of patients with herniation-associated radiculopathy.Level of Evidence: N/A.

UVB irradiation induces contralateral changes in galanin, substance P and c-fos immunoreactivity in rat dorsal root ganglia, dorsal horn and lateral spinal nucleus.

The selection of control group is crucial, as the use of an inadequate group may strongly affect the results. In this study we examine the effect on contralateral tissue protein levels, in a model of unilateral UVB irradiation, as the contralateral side is commonly used as a control. Previous studies have shown that UVB irradiation increases immunoreactivity for inflammatory regulated neuropeptides. Unilateral UVB irradiation of rat hind paw was performed and corresponding contralateral spinal cord and dorsal root ganglia (DRG) were collected 2-96 h after and investigated for changes in galanin, substance P and c-fos immunoreactivity. Control tissue was collected from naïve rats. Measurement of skin blood flow from contralateral heel hind paws (Doppler), revealed no change compared to naïve rats. However, UVB irradiation caused a significant reduction in the contralateral proportion of galanin immunopositive DRG neurons, at all-time points, as well as an increase in the contralateral spinal cord dorsal horn, around the central canal and in the lateral spinal nucleus (2-48 h). The contralateral proportion of SP positive DRG neurons and dorsal horn immunoreactivity was unchanged, whereas the lateral spinal nucleus area showed increased immunoreactivity (48 h). UVB irradiation also induced a slight contralateral upregulation of c-fos in the dorsal horn/central canal area (24 and 48 h). In summary, unilateral UVB irradiation induced contralateral changes in inflammatory/nociceptive neuropeptides in spinal cord and afferent pathways involved in pain signaling already within 24 h, a time point when also ipsilateral neurochemical/physiological changes have been reported for rats and humans.

Long-term Inhibition of Soleus H-reflex with Epidural Adhesiolysis and Pulsed Radiofrequency in Lumbosacral Neuropathic Pain.

INTRODUCTION: Scientific data about neurophysiological changes subsequent to pulsed radiofrequency (PRF) are still lacking. The goal of this study was to evaluate sural nerve conduction and Hoffmann reflex (H-reflex) in soleus muscle following adhesiolysis and PRF in patients with unilateral chronic lumbosacral L5-S1 neuropathic radiating pain. METHODS: Seventeen patients received two cycles of 240 seconds high-voltage PRF and epidural adhesiolysis. Sural nerve action potential (SNAP) and the ratio of maximum H-reflex to maximum M response (H/M ratio) as well as pain scores were collected in both lower limbs before, immediately following, and 1 month after the treatment. RESULTS: At follow-up, a significant reduction in numeric rating scale (NRS) and Douleur Neuropathique 4 Questions (DN4) scores was observed in 53% of patients reporting pain improvement of ≥ 30% over baseline. The H/M ratio was decreased in the affected limb following PRF (P = 0.01) and 1 month after the treatment (P = 0.04). A direct correlation was observed between H/M ratio variation and NRS score at follow-up in the treated limb (P = 0.04). No significant difference in sural nerve latency, amplitude, and velocity was detected between affected and normal side after treatment and at follow-up. CONCLUSIONS: Epidural adhesiolysis and PRF of the dorsal root ganglion seem to significantly affect spinal reflexes in patients with lumbosacral neuropathic radiating pain.

The effects of low intensity focused ultrasonic stimulation on dorsal root ganglion neurons and Schwann cells in vitro.

Satisfactory treatment of peripheral nerve injury (PNI) faces difficulties owing to the intrinsic biological barriers in larger injuries and invasive surgical interventions. Injury gaps >3 cm have low chances of full motor and sensory recovery, and the unmet need for PNI repair techniques which increase the likelihood of functional recovery while limiting invasiveness motivate this work. Building upon prior work in ultrasound stimulation (US) of dorsal root ganglion (DRG) neurons, the effects of US on DRG neuron and Schwann cell (SC) cocultures were investigated to uncover the role of SCs in mediating the neuronal response to US in vitro. Acoustic intensity-dependent alteration in selected neuromorphometrics of DRG neurons in coculture with SCs was observed in total outgrowth, primary neurites, and length compared to previously reported DRG monoculture in a calcium-independent manner. SC viability and proliferation were not impacted by US. Conditioned medium studies suggest secreted factors from SCs subjected to US impact DRG neuron morphology. These findings advance the current understanding of mechanisms by which these cell types respond to US, which may lead to new noninvasive US therapies for treating PNI.

Analgesic effect of Photobiomodulation Therapy: An in vitro and in vivo study.

Laser therapy, also known as Photobiomodulation (PBM) is indicated to reduce pain associated with different pathologies and applied using protocols that vary in wavelength, irradiance and fluence. Its mechanisms of action are still unclear and possibly able to directly impact on pain transmission, reducing nociceptor response. In our study, we examined the effect of two specific laser wavelengths, 800 and 970 nm, extensively applied in the clinical context and known to exert important analgesic effects. Our results point to mitochondria as the primary target of laser light in isolated dorsal root ganglion (DRG) neurons, reducing adenosine triphosphate content and increasing reactive oxygen species levels. Specifically, the 800 nm laser wavelength induced mitochondrial dysregulation, that is, increased superoxide generation and mitochondrial membrane potential. When DRG neurons were firstly illuminated by the different laser protocols and then stimulated with the natural transient receptor potential cation channel subfamily V member 1 (TRPV1) ligand capsaicin, only the 970 nm wavelength reduced the calcium response, in both amplitude and frequency. Consistent results were obtained in vivo in mice, by subcutaneous injection of capsaicin. Our findings demonstrate that the effect of PBM depends on the wavelength used, with 800 nm light mainly acting on mitochondrial metabolism and 970 nm light on nociceptive signal transmission.

X-ray induces mechanical and heat allodynia in mouse via TRPA1 and TRPV1 activation.

Radiotherapy-related pain is a common adverse reaction with a high incidence among cancer patients undergoing radiotherapy and remarkably reduces the quality of life. However, the mechanisms of ionizing radiation-induced pain are largely unknown. In this study, mice were treated with 20 Gy X-ray to establish ionizing radiation-induced pain model. X-ray evoked a prolonged mechanical, heat, and cold allodynia in mice. Transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 were significantly upregulated in lumbar dorsal root ganglion. The mechanical and heat allodynia could be transiently reverted by intrathecal injection of transient receptor potential vanilloid 1 antagonist capsazepine and transient receptor potential ankyrin 1 antagonist HC-030031. Additionally, the phosphorylated extracellular regulated protein kinases (ERK) and Jun NH2-terminal Kinase (JNK) in pain neural pathway were induced by X-ray treatment. Our findings indicated that activation of transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 is essential for the development of X-ray-induced allodynia. Furthermore, our findings suggest that targeting on transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 may be promising prevention strategies for X-ray-induced allodynia in clinical practice.

2 Hz EA Reduces Heroin Withdrawal-Induced Hyperalgesia and Heroin Relapse by Downregulating P2X3 Receptors in DRG Neurons.

Electroacupuncture (EA) has effective analgesic effects. Our previous study demonstrated that the upregulation of P2X3 receptors in the dorsal root ganglia (DRG) might participate in heroin withdrawal-induced hyperalgesia. The aim of this study is to further explore whether 2 Hz EA reduces heroin relapse associated with its analgesic effect and whether P2X3 receptors in the DRG are involved in this process. 2 Hz EA was adopted to treat the heroin SA rats in the present study. Heroin-seeking and pain sensitivity were evaluated. The expression of P2X3 receptors in the DRG was detected. Our results showed that compared with the control group, the reinstatement, thermal hyperalgesia, and mechanical allodynia of the heroin-addicted group were increased significantly. The expression of P2X3 receptors in the DRG was increased markedly. After being treated using 2 Hz EA, reinstatement was reduced, hyperalgesia was decreased, and the upregulated expression of P2X3 receptors in the DRG had decreased significantly compared to that in the heroin-addicted group. Consequently, our results indicated that 2 Hz EA was an effective method for treating heroin-induced hyperalgesia and helping prevent relapse, and the potential mechanism might be related to the downregulation of P2X3 receptor expression in the DRG.

Pulsed Radiofrequency on Dorsal Root Ganglion Relieved Neuropathic Pain Associated with Downregulation of the Spinal Interferon Regulatory Factor 8, Microglia, p38MAPK Expression in a CCI Rat Model.

BACKGROUND: Interferon regulatory factor 8 (IRF8), which is induced by peripheral nerve injury (PNI), plays a key role in activating spinal microglia to release inflammatory cytokines in a p38-dependent way, thereafter results in formation of central sensitization. Pulsed radiofrequency (PRF) on dorsal root ganglion (DRG) alleviates neuropathic pain and inhibits the microglial activation in chronic constriction injury (CCI) rats. However, the consequences of PRF on spinal IRF8 of CCI rats remains unknown. OBJECTIVE: We explore if PRF on DRG of rats with CCI could restrain IRF8, microglia, and p38 hyperactivity in the spinal cord to alleviate neuropathic pain. STUDY DESIGN: A randomized, controlled animal study. SETTING: Department of Pain Management, Fujian Provincial Hospital, Fujian Key Laboratory of Geriatrics, Provincial Clinic College of Fujian Medical University. METHODS: The changes in pain behaviors and the expressions of IRF8, Iba1 and p-p38 in the spinal cord of CCI rats which were administrated with antisense/ mismatch oligodeoxynucleotide of IRF8 were studied. Rats in CCI+AS ODN group, CCI+MM ODN group or CCI+NS group were intrathecally treated with antisense oligodeoxynucleotide of IRF8, mismatch oligodeoxynucleotide of IRF8 or same volume 0.9% NaCl once daily respectively, beginning from the day after nerve transection 12 hours and lasting for 7 days. The effects of PRF on L4-5 DRG of rats with CCI were investigated. PRF was applied adjacent to the L4-5 DRG at an intensity of 45 V for 6 minutes after CCI, whereas the control rats were treated without radiofrequency current. The withdrawal thresholds were studied and the spinal levels of IRF8, ionized calcium-binding adapter molecule 1 (Iba1, microglia characteristic marker) and p-p38 were calculated by ELISA, western blot, RT-PCR, and immunofluorescence. RESULTS: Intrathecal administration of antisense oligodeoxynucleotide of IRF8 led to the reversal of CCI-induced allodynia, lower activation of spinal microglia and p-p38. Withdrawal thresholds were partially recovered after a single PRF treatment for 14 days. CCI-induced IRF8 upregulation, microglia hyperactivity, and p38 phosphorylation in the spinal cord were reduced due to PRF treatment. However, PRF did not alter pain behaviors and pain signals in normal rats. LIMITATIONS: In our study, one time point was selected just to assess the levels of microglia, and p-p38. The changes of IRF8, microglia, p-p38 in the ipsilateral DRG were not investigated. A more detailed study on how PRF on the DRG could further relieve NP is needed. CONCLUSIONS: Restraining IRF8, microglia and p38 hyperactivity in the spinal cord of CCI rats involved in the contribution to the long-lasting analgesia of PRF. KEY WORDS: Neuropathic pain, pulsed radiofrequency, dorsal root ganglion, microglia, p38MAPK, Interferon regulatory factor 8, chronic constriction injury of sciatic nerve.

Comparison of efficacy of continuous epidural block and pulsed radiofrequency to the dorsal root ganglion for management of pain persisting beyond the acute phase of herpes zoster.

BACKGROUND: There is little evidence regarding the effectiveness of intervention methods in the treatment of zoster-related pain (ZAP) after the acute phase of zoster. Generally, if ZAP remains after more than 180 days from its onset, the likelihood of pain reduction is very low; this condition is considered as a "well established" post-herpetic neuralgia (PHN). Although the clinical efficacy of intrathecal steroid injection and spinal cord stimulation (SCS) for ZAP management has been reported, these interventions are not widely used due to inherent disadvantages. Continuous epidural block is widely used in clinical practice, and the effectiveness of pulsed radiofrequency (PRF) to the dorsal root ganglion (DRG) in the treatment of ZAP already has been reported. OBJECTIVES: The purpose of this study was to compare the clinical efficacy of continuous epidural block and DRG PRF beyond acute phase of zoster, bur before PHN was well established (from 30 days to180 days after zoster onset). STUDY DESIGN: Retrospective comparative study. METHODS: A total of 42 medical records were analyzed. Patients were divided into two groups according to the type of procedure utilized: continuous epidural block (continuous epidural group) and DRG PRF (PRF group). The clinical efficacy of the procedure was evaluated using a numeric rating scale (NRS) and the medication dose before and 1 to 6 months after the procedure. RESULTS: There was a significant decrease in the NRS value with time in both groups. However, this decrease was more significant in the PRF group than in the continuous epidural group. The medication doses decreased significantly in the PRF group over time, but not in the continuous epidural group. The rate of clinically meaningful PHN (NRS≥3) was also lower in the PRF group than in the continuous epidural group. CONCLUSIONS: This study revealed that DRG PRF was more effective than a continuous epidural block in treating ZAP after the acute phase of zoster. A neuromodulation method such as DRG PRF may be a useful option for reducing the progression of neuropathic changes caused by the persistent transmission of a pain signal after the acute phase of zoster.

The mechanistic basis for photobiomodulation therapy of neuropathic pain by near infrared laser light.

BACKGROUND AND OBJECTIVE: Various irradiances have been reported to be beneficial for the treatment of neuropathic pain with near infrared light. However, the mechanistic basis for the beneficial outcomes may vary based on the level of irradiance or fluence rate used. Using in vivo and in vitro experimental models, this study determined the mechanistic basis of photobiomodulation therapy (PBMT) for the treatment of neuropathic pain using a high irradiance. STUDY DESIGN/MATERIALS AND METHODS: In vitro experiments: Cultured, rat DRG were randomly assigned to control or laser treatment (LT) groups with different irradiation times (2, 5, 30, 60, or 120 seconds). The laser parameters were: output power = 960 mW, irradiance = 300 mW/cm2 , 808 nm wavelength, and spot size = 3 cm diameter/area = 7.07cm2 , with different fluences according to irradiation times. Mitochondrial metabolic activity was measured with the MTS assay. The DRG neurons were immunostained using a primary antibody to ß-Tubulin III. In vivo experiments: spared nerve injury surgery (SNI), an animal model of persistent peripheral neuropathic pain, was used. The injured rats were randomly divided into three groups (n = 5). (i) Control: SNI without LT; (ii) Short term: SNI with LT on day 7 and euthanized on day 7; (iii) Long term: SNI with LT on day 7 and euthanized on day 22. An 808 nm wavelength laser was used for all treatment groups. Treatment was performed once on day 7 post-surgery. The transcutaneous treatment parameters were: output power: 10 W, fluence rate: 270 mW/cm2 , treatment time: 120 seconds. The laser probe was moved along the course of the sciatic/sural nerve during the treatment. Within 1 hour of irradiation, behavior tests were performed to assess its immediate effect on sensory allodynia and hyperalgesia caused by SNI. RESULTS: In vitro experiments: Mitochondrial metabolism was significantly lower compared to controls for all LT groups. Varicosities and undulations formed in neurites of DRG neurons with a cell body diameter 30 µm or less. In neurites of DRG neurons with a cell body diameter of greater than 30 µm, varicosities formed only in the 120 seconds group. In vivo experiments: For heat hyperalgesia, there was a statistically significant reduction in sensitivity to the heat stimulus compared to the measurements done on day 7 prior to LT. A decrease in the sensitivity to the heat stimulus was found in the LT groups compared to the control group on days 15 and 21. For cold allodynia and mechanical hyperalgesia, a significant decrease in sensitivity to cold and pin prick was found within 1 hour after LT. Sensitivity to these stimuli returned to the control levels after 5 days post-LT. No significant difference was found in mechanical allodynia between control and LT groups for all time points examined. CONCLUSION: These in vitro and in vivo studies indicate that treatment with an irradiance/fluence rate at 270 mW/cm2 or higher at the level of the nerve can rapidly block pain transmission. A combination therapy is proposed to treat neuropathic pain with initial high irradiance/fluence rates for fast pain relief, followed by low irradiance/fluence rates for prolonged pain relief by altering chronic inflammation. Lasers Surg. Med. 49:516-524, 2017. © 2017 Wiley Periodicals, Inc.

Efficacy of Pulsed Radiofrequency Therapy to Dorsal Root Ganglion Adding to TENS and Exercise for Persistent Pain after Total Knee Arthroplasty.

The majority of patients achieve substantial pain relief and improved function after total knee arthroplasty (TKA), but a proportion continues to experience life-disturbing persistent postsurgical pain (PPSP) in the months and years after surgery. This study aimed to assess the efficacy of transcutaneous electrical nerve stimulation (TENS), exercise, and pulsed radiofrequency (PRF) treatment on pain severity, neuropathic pain, knee flexion range of motion (ROM), functional status, and patient satisfaction in patients with PPSP after TKA. This is a retrospective study of prospectively collected data. Patients who were identified retrospectively from hospital charts were divided into two groups: group 1 (n = 17) received TENS and exercise treatment and group 2 (n = 22) received TENS, exercise, and PRF application to the dorsal root ganglion (DRG). The following procedure-related parameters were collected from the special registry form: visual analog scale (VAS), Douleur Neuropathique 4 (DN4) questionnaire, knee flexion ROM, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and patient satisfaction scale scores. The mean follow-up was 253.8 ± 109 days. When the two groups were compared, a significant difference of at least 50% improvement in the VAS (activity) and a significant reduction in the DN4 scores following the last control examination were found in group 2. There was a significant reduction in total WOMAC scores in group 1 compared with group 2 for the four study periods. Higher scores for the patient satisfaction scale were found in group 1 compared with group 2 following the last control examination. Adding PRF to TENS and exercise therapy is useful in reducing the degree of pain and the neuropathic component of PPSP in patients with PPSP.

UVB irradiation induces rapid changes in galanin, substance P and c-fos immunoreactivity in rat dorsal root ganglia and spinal cord.

Recent studies have shown that UVB irradiation induces primary and secondary hyperalgesia in rats and humans peaking about 24h after UVB exposure. In the present study we investigated the changes in galanin, substance P and c-fos immunoreactivity in rat DRG and spinal cord at the L5 level 2-96h after UVB irradiation. UVB irradiation of the heel area in rats almost increased the skin blood flow two-fold 24h after irradiation as measured by laser Doppler technique. UVB irradiation induced a significant reduction of the proportion of galanin positive DRG neurons for all time points, except at 12h. In the spinal cord, UVB irradiation induced increased immunoreactivity for galanin in the dorsal horn, the area around the central canal and interestingly also in the lateral spinal nucleus 12-96h after exposure. For substance P the proportion of substance P positive neurons was unchanged but UVB irradiation induced increased substance P immunoreactivity in the dorsal part of the spinal cord 48h after irradiation. UVB irradiation also induced c-fos immunoreactivity in the dorsal horn and the area around the central canal 24 and 48h after exposure. This translational model of UVB irradiation will induce rapid changes of neuropeptides implicated in nociceptive signaling in areas known to be of importance for nociception in a time frame, about 24h after exposure, where also neurophysiological alteration have been described in humans and rats.

Comparative Effectivenesses of Pulsed Radiofrequency and Transforaminal Steroid Injection for Radicular Pain due to Disc Herniation: a Prospective Randomized Trial.

Transforaminal Epidural steroid injections (TFESI) have been widely adopted to alleviate and control radicular pain in accord with current guidelines. However, sometimes repeated steroid injections have adverse effects, and thus, this prospective randomized trial was undertaken to compare the effectivenesses of pulsed radiofrequency (PRF) administered to a targeted dorsal root ganglion (DRG) and TFESI for the treatment of radicular pain due to disc herniation. Subjects were recruited when first proved unsuccessful (defined as a score of > 4 on a visual analogue scale (VAS; 0-10 mm) and of > 30% according to the Oswestry Disability Index (ODI) or the Neck Disability Index (NDI)). Forty-four patients that met the inclusion criteria were enrolled. The 38 subjects were randomly assigned to receive either PRF (PRF group; n = 19) or additional TFESI (TFESI group; n = 19) and were then followed for 2, 4, 8, and 12 weeks. To evaluate pain intensity were assessed by VAS. ODI and NDI were applied to evaluate functional disability. Mean VAS scores for cervical and lumbar radicular pain were significantly lower 12 weeks after treatment in both study groups. NDI and ODI scores also declined after treatment. However, no statistically significant difference was observed between the PRF and TFESI groups in terms of VAS, ODI, or NDI scores at any time during follow-up. PRF administered to a DRG might be as effective as TFESI in terms of attenuating radicular pain caused by disc herniation, and its use would avoid the adverse effects of steroid.

Stimulation Frequency Alters the Dorsal Root Ganglion Neurite Growth and Directionality In Vitro.

OBJECTIVE: To improve peripheral nerve repair, new techniques to increase the speed of regeneration are required. Studies have shown that the electrical stimulation can enhance nerve regeneration; however, stimulation parameters that regulate the growth increases are unknown. The objective of this study was to examine dorsal root ganglion (DRG) neurite extension, directionality, and density after using methods to specifically control ac electrical field intensity and frequency exposure. METHODS: Chick DRG explants were exposed to 20-Hz, 200-Hz, 1-MHz, and 20-MHz sinusoidal electric field of 17.86 V/m, and tissue parameters were measured. RESULTS: Results show that neurite extension and directionality were influenced by frequency; however, the ratio of support cell emigration with respect to neurite extension from the DRG body was not. These results were further verified through finite-element modeling of intracellular calcium, which show that higher frequencies have minimal effect on intracellular calcium. CONCLUSION: In conclusion, these results demonstrate that 1) directional growth of neurites within EFs can be achieved, 2) high-frequency stimulation in megahertz does not enhance or impair the neurite growth, and 3) low-frequency stimulation affects the growth and directionality. SIGNIFICANCE: The significance of this study is the direct comparison of neurite extension after high stimulation frequencies (megahertz) with typical low-frequency fields (20 and 200 Hz), and modeling the results with finite-element modeling.

Comparative Effectivenesses of Pulsed Radiofrequency and Transforaminal Steroid Injection for Radicular Pain due to Disc Herniation: a Prospective Randomized Trial

Transforaminal Epidural steroid injections (TFESI) have been widely adopted to alleviate and control radicular pain in accord with current guidelines. However, sometimes repeated steroid injections have adverse effects, and thus, this prospective randomized trial was undertaken to compare the effectivenesses of pulsed radiofrequency (PRF) administered to a targeted dorsal root ganglion (DRG) and TFESI for the treatment of radicular pain due to disc herniation. Subjects were recruited when first proved unsuccessful (defined as a score of > 4 on a visual analogue scale (VAS; 0-10 mm) and of > 30% according to the Oswestry Disability Index (ODI) or the Neck Disability Index (NDI)). Forty-four patients that met the inclusion criteria were enrolled. The 38 subjects were randomly assigned to receive either PRF (PRF group; n = 19) or additional TFESI (TFESI group; n = 19) and were then followed for 2, 4, 8, and 12 weeks. To evaluate pain intensity were assessed by VAS. ODI and NDI were applied to evaluate functional disability. Mean VAS scores for cervical and lumbar radicular pain were significantly lower 12 weeks after treatment in both study groups. NDI and ODI scores also declined after treatment. However, no statistically significant difference was observed between the PRF and TFESI groups in terms of VAS, ODI, or NDI scores at any time during follow-up. PRF administered to a DRG might be as effective as TFESI in terms of attenuating radicular pain caused by disc herniation, and its use would avoid the adverse effects of steroid.

Comparative Effectivenesses of Pulsed Radiofrequency and Transforaminal Steroid Injection for Radicular Pain due to Disc Herniation: a Prospective Randomized Trial

Transforaminal Epidural steroid injections (TFESI) have been widely adopted to alleviate and control radicular pain in accord with current guidelines. However, sometimes repeated steroid injections have adverse effects, and thus, this prospective randomized trial was undertaken to compare the effectivenesses of pulsed radiofrequency (PRF) administered to a targeted dorsal root ganglion (DRG) and TFESI for the treatment of radicular pain due to disc herniation. Subjects were recruited when first proved unsuccessful (defined as a score of > 4 on a visual analogue scale (VAS; 0-10 mm) and of > 30% according to the Oswestry Disability Index (ODI) or the Neck Disability Index (NDI)). Forty-four patients that met the inclusion criteria were enrolled. The 38 subjects were randomly assigned to receive either PRF (PRF group; n = 19) or additional TFESI (TFESI group; n = 19) and were then followed for 2, 4, 8, and 12 weeks. To evaluate pain intensity were assessed by VAS. ODI and NDI were applied to evaluate functional disability. Mean VAS scores for cervical and lumbar radicular pain were significantly lower 12 weeks after treatment in both study groups. NDI and ODI scores also declined after treatment. However, no statistically significant difference was observed between the PRF and TFESI groups in terms of VAS, ODI, or NDI scores at any time during follow-up. PRF administered to a DRG might be as effective as TFESI in terms of attenuating radicular pain caused by disc herniation, and its use would avoid the adverse effects of steroid.

Optogenetic control of nerve growth.

Due to the limited regenerative ability of neural tissue, a diverse set of biochemical and biophysical cues for increasing nerve growth has been investigated, including neurotrophic factors, topography, and electrical stimulation. In this report, we explore optogenetic control of neurite growth as a cell-specific alternative to electrical stimulation. By investigating a broad range of optical stimulation parameters on dorsal root ganglia (DRGs) expressing channelrhodopsin 2 (ChR2), we identified conditions that enhance neurite outgrowth by three-fold as compared to unstimulated or wild-type (WT) controls. Furthermore, optogenetic stimulation of ChR2 expressing DRGs induces directional outgrowth in WT DRGs co-cultured within a 10 mm vicinity of the optically sensitive ganglia. This observed enhancement and polarization of neurite growth was accompanied by an increased expression of neural growth and brain derived neurotrophic factors (NGF, BDNF). This work highlights the potential for implementing optogenetics to drive nerve growth in specific cell populations.

Neurite growth acceleration of adult Dorsal Root Ganglion neurons illuminated by low-level Light Emitting Diode light at 645 nm.

The effect of a 645 nm Light Emitting Diode (LED) light irradiation on the neurite growth velocity of adult Dorsal Root Ganglion (DRG) neurons with peripheral axon injury 4-10 days before plating and without previous injury was investigated. The real amount of light reaching the neurons was calculated by taking into account the optical characteristics of the light source and of media in the light path. The knowledge of these parameters is essential to be able to compare results of the literature and a way to reduce inconsistencies. We found that 4 min irradiation of a mean irradiance of 11.3 mW/cm(2) (corresponding to an actual irradiance reaching the neurons of 83 mW/cm(2)) induced a 1.6-fold neurite growth acceleration on non-injured neurons and on axotomized neurons. Although the axotomized neurons were naturally already in a rapid regeneration process, an enhancement was found to occur while irradiating with the LED light, which may be promising for therapy applications. Dorsal Root Ganglion neurons (A) without previous injury and (B) subjected to a conditioning injury.

Repeated administration of IL-31 upregulates IL-31 receptor A (IL-31RA) in dorsal root ganglia and causes severe itch-associated scratching behaviour in mice.

We investigated the effects of repeated administration of interleukin-31 (IL-31) on itch-associated scratching counts (long-lasting scratching, LLS) and IL-31-related receptor mRNA expression in mice. Intra-dermal (i.d.) injection of IL-31 (100 and 300 ng/site) every 12 h for 3 days significantly increased LLS. Repeated administration of IL-31 also increased the expression of IL-31 receptor A (IL-31RA) and oncostatin M receptor beta (OSMRß) in dorsal root ganglia (DRG). After the repeated administration of IL-31 was discontinued, IL-31RA expression decreased and reached the baseline level 2 days after the last dose of IL-31. LLS changed along with DRG IL-31RA expression. Moreover, IL-31-induced IL-31RA protein expression was confirmed by Western blotting analysis. These data suggest that IL-31 upregulates IL-31RA expression in DRG neuron cell bodies, and cutaneous-injected IL-31-induced itching is enhanced by DRG IL-31RA expression in mice.